Novel compositions

ABSTRACT

Provided are pharmaceutical compositions comprising (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form. The compositions are formulated for providing a sustained release of enantiomerically pure (1R,5S)-1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane. The compositions are substantially free of the other (−) enantiomer of the compound.

BACKGROUND

(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane is an unbalancedtriple reuptake inhibitor with the most potency towards norepinephrinereuptake (NE), one-sixth as much towards dopamine reuptake (DA), andone-fourteenth as much towards serotonin reuptake (5-HT).

There remains a need for novel pharmaceutical compositions comprising(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free orpharmaceutically acceptable salt form.

BRIEF SUMMARY

Provided is a pharmaceutical composition comprising(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free orpharmaceutically acceptable salt form.

Further areas of applicability of the present disclosure will becomeapparent from the detailed description provided hereinafter. It shouldbe understood that the detailed description and specific examples, whileindicating the preferred embodiment of this disclosure, are intended forpurposes of illustration only and are not intended to limit the scope ofthis disclosure.

DETAILED DESCRIPTION

The following description of the preferred embodiment(s) is merelyexemplary in nature and is in no way intended to limit the invention,its application, or uses.

As used throughout, ranges are used as shorthand for describing each andevery value that is within the range. Any value within the range can beselected as the terminus of the range. In addition, all references citedherein are hereby incorporated by referenced in their entireties. In theevent of a conflict in a definition in the present disclosure and thatof a cited reference, the present disclosure controls.

(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, also known as(+)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, is shown as Formula Ibelow.

“(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane” and“(+)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane” are usedinterchangeably herein.

(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane is an unbalancedtriple reuptake inhibitor with the most potency towards norepinephrinereuptake (NE), one-sixth as much towards dopamine reuptake (DA), andone-fourteenth as much towards serotonin reuptake (5-HT).

(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane may be synthesizedas described in U.S. Pat. No. 8,461,196 or International Publication No.WO 2013/019271, both of which are incorporated herein by reference intheir entirety.

As used herein, “substantially free of the corresponding (−) enantiomer”means more of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane thanthe corresponding (−) enantiomer, i.e.,(1S,5R)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane. In someembodiments, “substantially free of the corresponding (−) enantiomer”means containing no more than 20% w/w (weight/weight) of thecorresponding (−) enantiomer, in free or pharmaceutically acceptablesalt form, e.g., no more than 10% w/w of the corresponding (−)enantiomer, in free or pharmaceutically acceptable salt form, e.g., nomore than 5% w/w of the corresponding (−) enantiomer, in free orpharmaceutically acceptable salt form, e.g., no more than 2% w/w of thecorresponding (−) enantiomer, in free or pharmaceutically acceptablesalt form, e.g., no more than 1% w/w of the corresponding (−)enantiomer, in free or pharmaceutically acceptable salt form.

As used herein, “(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane”embraces the compound in any form, for example, free or pharmaceuticallyacceptable salt form, e.g., as a pharmaceutically acceptable acidaddition salt. Pharmaceutically acceptable salts are known in the artand include salts that are physiologically acceptable at the dosageamount and form to be administered, for example, hydrochloride salts.

As used herein, “(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane”is also to be understood as embracing the compound in crystalline andamorphous form including, for example, polymorphs, solvates (includinghydrates), unsolvated polymorphs (including anhydrates), conformationalpolymorphs, and amorphous forms of the compounds, as well as mixturesthereof. “Crystalline form” and “polymorph” may be used interchangeablyherein, and are meant to include all crystalline forms of(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free orpharmaceutically acceptable salt form, including, for example,polymorphs, solvates (including hydrates), unsolvated polymorphs(including anhydrates), and conformational polymorphs, as well asmixtures thereof, unless a particular crystalline form is referred to.

Crystalline and amorphous forms of(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane may be used in anycombination or in forms that are substantially free of one or more ofthe other crystalline forms or free of the amorphous form.

(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane may in some casesalso exist in prodrug form. Prodrugs are considered to be any covalentlybonded carriers that release the active parent drug in vivo.

As used herein, “concurrently” means the compounds are administeredsimultaneously or within the same composition. In some embodiments, thecompounds are administered simultaneously. In some embodiments, thecompounds are administered within the same composition.

The nominal viscosity of polymers, e.g., hydroxypropyl methylcellulosemay be measured, for example, at a 2% concentration in water at 20° C.according to the U.S. Pharmacopeia and by other techniques known tothose skilled in the art.

Particle size measurements may be made, for example, by laserdiffraction and by other techniques known to those skilled in the art.

In some embodiments, the pharmaceutical compositions disclosed hereincomprising (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, infree or pharmaceutically acceptable salt form, may be administered byany suitable route, including orally, parenterally, transdermally, or byinhalation, including by sustained release, although various other knowndelivery routes, devices and methods can likewise be employed. In someembodiments, provided is a sustained release pharmaceutical composition,e.g., an oral sustained release pharmaceutical composition, comprising(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free orpharmaceutically acceptable salt form, which provides therapeuticallyeffective levels of(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane over a sustaineddelivery period of approximately 6 hours or longer, e.g., 8 hours orlonger, e.g., 12 hours or longer, e.g., 18 hours or longer, e.g., 24hours or longer.

In some embodiments,(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free orpharmaceutically acceptable salt form, is released from a pharmaceuticalcomposition as disclosed herein and delivered into the blood plasma orother target site of activity in the subject (including, but not limitedto, areas of the brain such as the prefrontal cortex, frontal cortex,thalamus, striatum, ventral tegmental area, other cortical areas,hippocampus, hypothalamus, or nucleus accumbens) in a sustained releaseprofile characterized in that from about 0% to 20% of the activecompound is released and delivered (as determined, e.g., by measuringblood plasma levels) within 0 to 2 hours, from 20% to 50% of the activecompound is released and delivered within about 2 to 12 hours, from 50%to 85% of the active compound is released and delivered within about 3to 20 hours, and greater than 75% of the active compound is released anddelivered within about 5 to 18 hours.

In some embodiments,(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free orpharmaceutically acceptable salt form, is released from a pharmaceuticalcomposition as disclosed herein and delivered into the blood plasma orother target site of activity in the subject (including, but not limitedto, areas of the brain such as the prefrontal cortex, frontal cortex,thalamus, striatum, ventral tegmental area, other cortical areas,hippocampus, hypothalamus, or nucleus accumbens) in a sustained releaseprofile characterized in that at least 20% of the active compound isreleased and delivered (as determined, e.g., by measuring blood plasmalevels) within 4 or less hours after administration, e.g., at leastabout 30%, e.g., at least about 40%, e.g., about 20-80%, e.g., about30-70%, e.g., about 40-60% is released and delivered within 4 hours orless after administration.

In some embodiments,(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free orpharmaceutically acceptable salt form, is released from a pharmaceuticalcomposition as disclosed herein and delivered into the blood plasma orother target site of activity in the subject (including, but not limitedto, areas of the brain such as the prefrontal cortex, frontal cortex,thalamus, striatum, ventral tegmental area, other cortical areas,hippocampus, hypothalamus, or nucleus accumbens) in a sustained releaseprofile characterized in that at least 50% of the active compound isreleased and delivered (as determined, e.g., by measuring blood plasmalevels) within 8 hours or less after administration, e.g., at leastabout 60%, e.g., at least about 70%, e.g., at least about 80%, e.g.,about 50-90%, e.g., about 60-90%, e.g., about 60-80% is released anddelivered within 8 hours or less after administration.

In some embodiments, at least 20% of(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, e.g., at leastabout 30%, e.g., at least about 40%, e.g., about 20-80%, e.g., about30-70%, e.g., about 30-60%, e.g., about 40-60%, e.g., about 50-60%,e.g., about 50%, e.g., about 60%, is released and dissolved within 4hours or less (e.g., within about 2-4 hours, e.g., about within 3-4hours, e.g., about 4 hours) from a pharmaceutical composition asdisclosed herein as measured in 900 mL water using USP Apparatus 2paddle, at 50 rpm and at 37° C.±0.5. In addition, in some embodiments,at least 50% of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane,e.g., at least about 60%, e.g., at least about 70%, e.g., at least about80%, e.g., about 50-90%, e.g., about 60-90%, e.g., about 60-80% isreleased and dissolved within 8 hours or less (e.g., within about 6-8hours, e.g., within about 7-8 hours, e.g., about 8 hours) from apharmaceutical composition as disclosed herein as measured in 900 mLwater using USP Apparatus 2 paddle, at 50 rpm and 37° C.±0.5.

In some embodiments, the C_(max) of(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free orpharmaceutically acceptable salt form, provided after administration ofa sustained release pharmaceutical composition comprising(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free orpharmaceutically acceptable salt form, as disclosed herein is less thanabout 80%, e.g., less than about 75%, e.g., less than about 60%, e.g.,less than about 50%, e.g., less than about 40%, e.g., less than about30% of the C_(max) obtained after administering an equivalent dose of(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free orpharmaceutically acceptable salt form, in an immediate releasepharmaceutical composition. In some embodiments, the C_(max) of(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free orpharmaceutically acceptable salt form, provided after administration ofa sustained release pharmaceutical composition comprising(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free orpharmaceutically acceptable salt form, as disclosed herein is about20-80%, e.g., is about 30-80%, e.g., is about 20-70% e.g., is about30-70%, e.g., is about 30-60%, e.g., is about 30-50%, e.g., is about30-40%, of the C_(max) obtained after administering an equivalent doseof (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free orpharmaceutically acceptable salt form, in an immediate releasepharmaceutical composition.

(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free orpharmaceutically acceptable salt form, provided after administration ofa sustained release pharmaceutical composition comprising(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free orpharmaceutically acceptable salt form, as disclosed herein is less thanabout 50%, e.g., less than about 40%, e.g., less than about 30%, of theC_(max) obtained after administering an equivalent dose of(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free orpharmaceutically acceptable salt form, in an immediate releasepharmaceutical composition. In some embodiments, the C_(max) of(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free orpharmaceutically acceptable salt form, provided after administration ofa sustained release pharmaceutical composition comprising(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free orpharmaceutically acceptable salt form, as disclosed herein is about20-50%, e.g., is about 30-50%, e.g., is about 30-40%, of the C_(max)obtained after administering an equivalent dose of(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free orpharmaceutically acceptable salt form, in an immediate releasepharmaceutical composition.

In some embodiments, the pharmaceutical composition comprising(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free orpharmaceutically acceptable salt form, e.g., a sustained releasepharmaceutical composition, comprises a lubricant, e.g., magnesiumstearate, a carrier, e.g., lactose monohydrate, or a combinationthereof.

Provided is a pharmaceutical composition (Composition 1), e.g., asustained release pharmaceutical composition, comprising(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free orpharmaceutically acceptable salt form.

Further provided is Composition 1 as follows:

-   1.1 Composition 1 wherein the composition is sustained release.-   1.2 Composition 1 or 1.1 wherein the pharmaceutical composition is    substantially free of the corresponding (−) enantiomer.-   1.3 Composition 1, 1.1, or 1.2 wherein the composition comprises    less than or equal to 20% w/w of the corresponding (−) enantiomer.-   1.4 Any of Compositions 1 or 1.1-1.3 wherein the composition    comprises less than or equal to 10% w/w of the corresponding (−)    enantiomer.-   1.5 Any of Compositions 1 or 1.1-1.4 wherein the composition    comprises less than or equal to 5% w/w of the corresponding (−)    enantiomer.-   1.6 Any of Compositions 1 or 1.1-1.5 wherein the composition    comprises less than or equal to 2% w/w of the corresponding (−)    enantiomer.-   1.7 Any of Composition 1 or 1.1-1.6 wherein the composition    comprises less than or equal to 1% w/w of the corresponding (−)    enantiomer.-   1.8 Any of Compositions 1 or 1.1-1.7 wherein    (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane is in    pharmaceutically acceptable salt form.-   1.9 Composition 1.8 wherein    (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane in    pharmaceutically acceptable salt form is an acid addition salt.-   1.10 Composition 1.9 wherein    (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane in    pharmaceutically acceptable salt form is    (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride.-   1.11 Any of Compositions 1 or 1.1-1.10 comprising 1 mg to 1800 mg,    e.g., 10 mg to 1800 mg, e.g., 25 mg to 1800 mg, e.g., 10 mg to 1600    mg, e.g., 10 mg to 1200 mg, e.g., 50 mg to 1200 mg, e.g., 50 mg to    1000 mg, e.g., 75 mg to 1000 mg, e.g., 75 mg to 800 mg, e.g., 75 mg    to 500 mg, e.g., 100 mg to 750 mg, e.g., 100 mg to 500 mg, e.g., 100    mg to 400 mg, e.g., 100 mg to 300 mg, e.g., 100 mg to 200 mg, of    (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free or    pharmaceutically acceptable salt form.-   1.12 Any of Compositions 1 or 1.1-1.11 comprising 75 mg to 1000 mg,    e.g., 100 mg to 600 mg, e.g., 100 mg to 400 mg, e.g., 100 mg to 200    mg, of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in    free or pharmaceutically acceptable salt form.-   1.13 Any of Compositions 1 or 1.1-1.11 comprising 50 mg to 600 mg,    e.g., 100 mg to 600 mg, e.g., 100 mg to 400 mg, e.g., 100 mg to 200    mg, of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in    free or pharmaceutically acceptable salt form.-   1.14 Any of Compositions 1 or 1.1-1.11 comprising 5 mg to 500 mg,    e.g., 5 mg to 10 mg, e.g, 10 mg to 25 mg, e.g., 30 mg to 50 mg,    e.g., 10 mg to 300 mg, e.g., 25 mg to 300 mg, e.g., 50 mg to 100 mg,    e.g., 100 mg to 250 mg, e.g., 250 mg to 500 mg, of    (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free or    pharmaceutically acceptable salt form.-   1.15 Any of Compositions 1 or 1.1-1.10 for administration of 0.5    mg/kg to 20 mg/kg per day, e.g., 1 mg/kg to 15 mg/kg per day, e.g.,    1 mg/kg to 10 mg/kg per day, e.g., 2 mg/kg to 20 mg/kg per day,    e.g., 2 mg/kg to 10 mg/kg per day, e.g., 3 mg/kg to 15 mg/kg per    day, of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in    free or pharmaceutically acceptable salt form.-   1.16 Any of Compositions 1 or 1.1-1.15 comprising less than 50% w/w    of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free or    pharmaceutically acceptable salt form, e.g., less than about 40%    w/w, e.g., less than about 30% w/w, less than about 20% w/w, e.g.,    about 1-40% w/w, e.g., about 5-40% w/w, e.g., about 10-30% w/w,    e.g., about 15-25% w/w, e.g., about 15-20% w/w, e.g., about 17% w/w,    e.g., about 25% w/w.-   1.17 Any of Compositions 1 or 1.1-1.16 further comprising    hydroxypropyl methylcellulose (e.g., hypromellose HPMC K4M).-   1.18 Composition 1.17 wherein the composition comprises at least 10%    w/w of the hydroxypropyl methylcellulose, e.g., about 10-50% w/w,    e.g., about 10-40% w/w, e.g., about 20-50% w/w, e.g., about 20-40%    w/w, e.g., about 30-40% w/w, e.g., about 37% w/w.-   1.19 Composition 1.17 or 1.18 wherein the degree of methoxy    substitution of the hydroxypropyl methylcellulose is 19-24%.-   1.20 Any of Compositions 1.17-1.19 wherein the degree of    hydroxypropoxy substitution of the hydroxypropyl methylcellulose is    4-12%.-   1.21 Any of Compositions 1.17-1.20 wherein the hydroxypropyl    methylcellulose is hypromellose 2208.-   1.22 Any of Compositions 1.17-1.21 wherein the hydroxypropyl    methylcellulose has a nominal viscosity of 4,000 mPA·s.-   1.23 Any of Compositions 1.17-1.21 wherein the hydroxypropyl    methylcellulose has a viscosity of 2,000-6,000 mPA·s, e.g., about    2,600 to 5,000 mPA·s, e.g., about 2,663 to 4,970 mPA·s.-   1.24 Any of Compositions 1 or 1.1-1.23 wherein the composition    further comprises lactose (e.g., alpha-lactose monohydrate).-   1.25 Composition 1.24 wherein the composition comprises at least 10%    w/w of the alpha-lactose monohydrate, e.g., about 10-80% w/w, e.g.,    about 20-70% w/w, e.g., about 20-60% w/w, e.g., about 20-50% w/w,    e.g., about 20-40% w/w, e.g., about 20-30% w/w, e.g., about 30-70%    w/w, e.g., about 30-60% w/w, e.g., about 30-50% w/w, e.g., about    30%-40% w/w, e.g., about 37% w/w.-   1.26 Composition 1.24 or 1.25 wherein the composition comprises    milled alpha-lactose monohydrate.-   1.27 Any of Compositions 1 or 1.1-1.26 wherein the composition    comprises a co-processed mixture of hydroxpropyl methylcellulose and    alpha-lactose monohydrate (e.g., Retalac).-   1.28 Composition 1.27 wherein the mixture comprises equal parts of    the hydroxpropyl methylcellulose and alpha-lactose monohydrate.-   1.29 Composition 1.27 or 1.28 wherein the mixture comprises    particles of hydroxpropyl methylcellulose and alpha-lactose    monohydrate with d₅₀ (median diameter) in the range of 100 μm to 200    μm, e.g., about 125 μm.-   1.30 Any of Compositions 1.27-1.29 wherein the mixture comprises    particles of hydroxpropyl methylcellulose and alpha-lactose    monohydrate wherein the particle size distribution is as follows:    -   <63 μm≦25%    -   <100 μm: 35%    -   <250 μm≧80%.-   1.31 Any of Compositions 1.27-1.30 wherein the composition comprises    at least 20% w/w of the mixture, e.g., about at least 30% w/w, e.g.,    at least about 40% w/w, e.g., at least about 50% w/w, e.g., at least    about 60% w/w, e.g., at least about 70% w/w, e.g, at least about 80%    w/w, e.g., about 20-90% w/w, e.g., about 30-80% w/w, e.g., about    40-80% w/w, e.g., about 50-80% w/w, e.g., about 60-80% w/w, e.g.,    about 70-80% w/w, e.g., about 75% w/w.-   1.32 Any of Compositions 1 or 1.1-1.31 wherein the composition    further comprises a lubricant, e.g., magnesium stearate.-   1.33 Composition 1.32 wherein the lubricant is one or more of    glyceryl behenate, magnesium stearate, talc, and sodium stearyl    fumarate, e.g, magnesium stearate.-   1.34 Composition 1.32 or 1.33 wherein the composition comprises less    than 10% w/w of the lubricant, e.g., less than about 5% w/w, less    than about 3% w/w, less than about 1% w/w, e.g., about 0.1 to 1%    w/w, e.g., about 0.1 to 0.8% w/w, e.g., about 0.5% w/w.-   1.35 Any of Compositions 1.32-1.34 wherein the composition comprises    less than 10% w/w of magnesium stearate, e.g., less than about 5%    w/w, less than about 3% w/w, less than about 1%, e.g., about 0.1 to    1% w/w, e.g., about 0.1 to 0.8% w/w, e.g., about 0.5% w/w.-   1.36 Any of Compositions 1 or 1.1-1.35 wherein the composition    further comprises one or more of a diluent, disintegrant, binder,    and modified release agent.-   1.37 Composition 1.36 wherein the diluent is one or more of mannitol    (e.g., Pearlitol 300 DC), micro-crystalline cellulose (e.g., Avicel    pH 102), and pre-gelatinized starch (e.g., Starch 1500).-   1.38 Composition 1.36 wherein the disintegrant is one or both of    crospovidone (e.g., Polyplasdone XL-10) and sodium starch glycolate    (e.g., Explotab).-   1.39 Composition 1.36 wherein the binder is polyvinylpyrrolidone    (e.g., Povidone K29/32).-   1.40 Composition 1.36 wherein the modified release agent is one or    more of hydroxypropyl cellulose (e.g., Klucel EXF, Klucel MXF and/or    Klucel HXF) and hydroxypropyl methylcellulose (e.g., Methocel K100M,    Methocel K4M PREM, Methocel K15M PREM CR).-   1.41 Composition 1.36 or 1.40 wherein the composition comprises at    least 5% w/w of the modified release agent, e.g., about 5-60% w/w,    e.g., about 10-50% w/w, e.g., about 10-40% w/w.-   1.42 Composition 1.40 or 1.41 wherein the modified release agent is    hydroxypropyl methylcellulose.-   1.43 Composition 1.42 wherein the degree of methoxy substitution of    the hydroxypropyl methylcellulose is 19-24%.-   1.44 Composition 1.42 or 1.43 wherein the degree of hydroxypropoxy    substitution of the hydroxypropyl methylcellulose is 4-12%.-   1.45 Any of Compositions 1.42-1.44 wherein the hydroxypropyl    methylcellulose is hypromellose 2208.-   1.46 Any of Compositions 1.42-1.45 wherein the hydroxypropyl    methylcellulose has a viscosity of 75,000-140,000 mPA·s.-   1.47 Any of Compositions 1.42-1.45 wherein the hydroxypropyl    methylcellulose has a viscosity of 2,000-6,000 mPA·s, e.g., about    2,600 to 5,000 mPA·s, e.g., about 2,663 to 4,970 mPA·s.-   1.48 Any of Compositions 1.42-1.45 wherein the hydroxypropyl    methylcellulose has a viscosity of 12,000-26,000 mPA·s, e.g., about    13,000 to 25,000 mPA·s, e.g., about 13,275 to 24,780 mPA·s.-   1.49 Any of Compositions 1.42-1.45 wherein the hydroxypropyl    methylcellulose has a viscosity of 100,000 cps.-   1.50 Any of Compositions 1.42-1.45 wherein the hydroxypropyl    methylcellulose has a viscosity of 3,600 cps.-   1.51 Any of Compositions 1.42-1.45 wherein the hydroxypropyl    methylcellulose has a viscosity of 18,000 cps.-   1.52 Composition 1.36, 1.40, or 1.41 wherein the modified release    agent is hydroxypropyl cellulose (e.g., Klucel EXF, Klucel MXF    and/or Klucel HXF).-   1.53 Any of Compositions 1 or 1.1-1.52 for administration once,    twice, three, or four times daily.-   1.54 Any of Compositions 1 or 1.1-1.53 further comprising another    drug.-   1.55 Any of Compositions 1 or 1.1-1.54 wherein the composition    further comprises an mGluR1 antagonist, an mGluR2/3 antagonist, an    mGluR5 antagonist, an AMPA receptor positive modulator, an NMDA    receptor antagonist, a tetracycline antibiotic, an α2-adrenergic    agonist, an antipsychotic, an anti-depressant (e.g., a selective    serotonin reuptake inhibitor (SSRI), a serotonin-norepinephrine    reuptake inhibitor (SNRI), or a tricyclic anti-depressant), a    benzodiazepine, an anti-convulsant, a mood stabilizer, a    gamma-aminobutyric acid (GABA) agonist e.g., a GABA-B agonist, a    GABA modulator, a stimulant, a 3-blocker, a hormone, or a    combination thereof.-   1.56 Any of Compositions 1 or 1.1-1.55 wherein the composition    further comprises fenobam, mavoglurant (AFQ056), dipraglurant,    R04917523, STX107, 2-methyl-6-phenylethynyl pyridine (MPEP), CX516,    memantine, acamprosate, minocycline, clonidine, guanfacine,    aripiprazole, risperidone, citalopram, escitalopram, fluoxetine,    sertraline, fluovoxamine, paroxetine, trazodone, bupropion,    imipramine, amitriptyline, venlafaxine, nefazodone, duloxetine,    venlafaxine, carbamazepine, lamotrigine, valproic acid, sodium    valproate, lithium, quetiapine, folic acid, L-acetylcarnitine,    melatonin, arbaclofen, donepezil hydrochloride, alpha-tocopherol,    methylphenidate, amphetamine mixed salts (e.g., Adderall),    dextroamphetamine, risperidone, olanzapine, ziprasidone, buspirone,    filuzole, metadoxine, primidone, topiramate, estradiol, cyclic    medroxyprogesterone, or a combination thereof.-   1.57 Any of Compositions 1 or 1.1-1.56 further comprising an mGluR5    antagonist.-   1.58 Composition 1.57 further comprising fenobam, mavoglurant    (AFQ056), dipraglurant, R04917523, STX107, 2-methyl-6-phenylethynyl    pyridine (MPEP), or a combination thereof.-   1.59 Composition 1.58 further comprising R04917523, mavoglurant    (AFQ056), or a combination thereof.-   1.60 Any of Compositions 1 or 1.1-1.59 further comprising a GABA-B    agonist.-   1.61 Composition 1.60 comprising arbaclofen.-   1.62 Any of Compositions 1 or 1.1-1.61 further comprising a GABA    modulator.-   1.63 Composition 1.62 further comprising acamprosate.-   1.64 Any of Compositions 1 or 1.1-1.63 further comprising    minocycline.-   1.65 Any of Compositions 1 or 1.1-1.64 wherein the C_(max) of    (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free or    pharmaceutically acceptable salt form, provided after administration    of the composition is less than about 80%, e.g., less than about    75%, e.g., less than about 60%, e.g., less than about 50%, e.g.,    less than about 40%, e.g., less than about 30%, e.g., is about    20-80%, e.g., is about 30-80%, e.g., is about 20-70% e.g., is about    30-70%, e.g., is about 30-60%, e.g., is about 30-50%, e.g., is about    30-40%, of the C_(max) obtained after administering an equivalent    dose of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in    free or pharmaceutically acceptable salt form, in an immediate    release pharmaceutical composition.-   1.66 Any of Compositions 1 or 1.1-1.65 wherein the C_(max) of    (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free or    pharmaceutically acceptable salt form, provided after administration    of a sustained release pharmaceutical composition comprising    (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free or    pharmaceutically acceptable salt form, is less than about 50%, e.g.,    less than about 40%, e.g., less than about 30%, e.g., about 20-50%,    e.g., about 30-50%, e.g., about 30-40%, of the C_(max) obtained    after administering an equivalent dose of    (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free or    pharmaceutically acceptable salt form, in an immediate release    pharmaceutical composition.-   1.67 Composition 1 wherein the composition comprises 25% w/w    (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride,    74.5% w/w of an equal parts mixture of hydroxypropyl methylcellulose    and alpha-lactose monohydrate, and 0.5% w/w magnesium stearate.-   1.68 Any of Compositions 1 or 1.1-1.67 for use in indications as    described in U.S. Pat. No. 8,461,196, International Publication No.    WO 2013/019271, and International Patent Application No. PCT/US    14/69401, the contents of each of which are hereby incorporated by    reference.

EXAMPLES Example 1

Sustained release pharmaceutical compositions comprising(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride maybe made utilizing a direct blend process, with screening of theexcipients and (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexanehydrochloride through a Quadro 197S Co-Mil, and blending in a V-shellblender prior to compression on a rotary tablet press.

Example 2 Sustained Release Pharmaceutical Composition Comprising(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride

Concentration Tablet Unit Ingredient (% W/W) Weight (mg)(1R,5S)-1-(naphthalen-2-  25% 100 yl)-3-azabicyclo[3.1.0]hexanehydrochloride Lactose Monohydrate, NF 74.5%  298 Hypromellose, NF (as50/50 premix - RetaLac ®) Magnesium Stearate, NF  0.5% 2 (Hyqual ®Vegetable source) Total 100% 400

HPLC conditions for dissolution and dissolution conditions for Examples3-9 are set forth in Tables 1 and 2.

TABLE 1 HPLC Conditions Dissolution Item Setting Column Waters XBridgeC18 3.0 × 150 mm 3.5 μm Mobile Phase MPA: 6 mM Ammonium Formate; 95%Water, 5% CAN MPB: 5 mM Ammonium Formate; 5% Water, 95% ACN Flow RateSee Gradient Detection 226 nm Column Temp. 40° C. Run Time 42 minutesInjection Volume 20 μL Flow Rate Gradient Time % MPA % MPB (mL/min) 0 955 0.8 30 50 50 0.8 30.1 5 95 0.8 35 5 95 1.2 35.1 95 5 0.8 42 95 5 0.8

TABLE 2 Dissolution Testing Conditions Item Setting/Condition MediaWater Volume 900 mL Speed 50 rpm Apparatus USP, App. 2, Paddle Temp. 37°C. ± 0.5

Example 3 Sustained Release Pharmaceutical Composition Comprising(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride

Manufacture by a direct blend process. Compress on Dynamic Exim rotarytablet press using concave ⅜″ tooling. Compress at a target weight of300 mg (+15 mg) and target hardness of approximately 8 kp±2 kp.

Concentration Tablet Unit Ingredient (% W/W) Weight (mg)(1R,5S)-1-(naphthalen-2- 16.7% 50 yl)-3-azabicyclo[3.1.0]hexanehydrochloride Lactose Monohydrate, NF 82.8% 248.5 Hypromellose, NF (as50/50 premix - RetaLac ®) Magnesium Stearate, NF  0.5% 1.5 Total  100%300

TABLE 3 Dissolution Data: 12-hour dissolution profile Numerical DataVessel 1 hr 2 hr 4 hr 6 hr 8 hr 12 hr 1 23 35 52 65 74 84 2 22 33 51 6473 84 3 21 34 50 64 73 84 Ave 22 34 51 64 73 84 % RSD 3.0 2.3 1.8 1.00.6 0.2

Example 4 Sustained Release Pharmaceutical Composition Comprising(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride

Manufacture by a direct blend process. Compress on Dynamic Exim rotarytablet press using concave ⅜″ tooling. Compress at a target weight of300 mg (±15 mg) and target hardness of approximately 8 kp±2 kp.

Concentration Tablet Unit Ingredient (% W/W) Weight (mg)(1R,5S)-1-(naphthalen-2- 16.7% 50 yl)-3-azabicyclo[3.1.0]hexanehydrochloride Lactose Monohydrate, NF 42.8% 128.4 Hypromellose, NF (as50/50 premix - RetaLac ®) Lactose Monohydrate, 315 SD 40.0% 120.0Magnesium Stearate, NF  0.5% 1.5 Total  100% 300

TABLE 4 Vessel 1 hr 2 hr 4 hr 6 hr 8 hr 12 hr 24 hr 1 32 48 66 78 85 9499 2 30 45 66 79 90 84 96 3 33 48 70 79 89 84 89 Ave 32 47 67 78 88 8795 % RSD 3.6 4.6 3.9 0.8 2.6 6.8 5.4

Example 5 Sustained Release Pharmaceutical Composition Comprising(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride

Manufacture by a direct blend process. Compress on Dynamic Exim rotarytablet press using concave ⅜″ tooling. Compress at a target weight of300 mg (+15 mg) and target hardness of approximately 8 kp±2 kp.

Concentration Tablet Unit Ingredient (% W/W) Weight (mg)(1R,5S)-1-(naphthalen-2- 16.7% 50 yl)-3-azabicyclo[3.1.0]hexanehydrochloride Lactose Monohydrate, NF 52.8% 158.5 Hypromellose, NF (as50/50 premix - RetaLac ®) Klucel HXF HPC 30.0% 90.0 Magnesium Stearate,NF  0.5% 1.5 Total  100% 300

TABLE 5 Vessel 1 hr 2 hr 4 hr 6 hr 8 hr 12 hr 24 hr 1 29 46 67 75 92 101105 2 29 43 65 74 91 94 106 3 30 43 65 75 87 101 105 Ave 30 44 66 75 9099 105 % RSD 2.0 3.5 1.6 0.7 3.0 4.3 0.6

Example 6 Sustained Release Pharmaceutical Composition Comprising(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride

Concentration Tablet Unit Ingredient (% W/W) Weight (mg)(1R,5S)-1-(naphthalen-2- 16.7% 50 yl)-3-azabicyclo[3.1.0]hexanehydrochloride Lactose Monohydrate, 315 SD 41.4% 124.25 HPMC K4M 41.4%124.25 Magnesium Stearate, NF  0.5% 1.5 Total  100% 300

TABLE 6 Vessel 1 hr 2 hr 4 hr 6 hr 8 hr 12 hr 24 hr 1 24 37 55 68 78 8892 2 21 33 51 63 76 92 95 3 22 34 52 62 77 93 100 4 24 38 56 72 86 100100 5 22 34 51 63 71 84 88 6 23 36 55 66 75 98 104 Ave 23 35 53 66 77 9296 % RSD 5.2 4.9 4.2 5.7 6.4 6.4 6.1

Example 7 Sustained Release Pharmaceutical Composition Comprising(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride

Concentration Tablet Unit Ingredient (% W/W) Weight (mg)(1R,5S)-1-(naphthalen-2- 33.3% 100 yl)-3-azabicyclo[3.1.0]hexanehydrochloride Lactose Monohydrate, NF 66.2% 198.5 Hypromellose, NF (as50/50 premix - RetaLac ®) Magnesium Stearate, NF  0.5% 1.5 (Hyqual ®Vegetable source) Total  100% 300

TABLE 7 Vessel 1 hr 2 hr 4 hr 6 hr 8 hr 12 hr 24 hr 1 21 33 53 69 84 — —2 21 34 54 68 81 — — 3 23 35 57 69 80 — — 4 22 31 54 68 83 — — 5 22 3556 71 83 — — 6 23 36 57 69 87 — — Ave 22 34 55 69 83 — — % RSD 5.0 4.83.6 1.5 3.0 — — NOTE: 12 and 24 hour pulls not performed

Example 8 Sustained Release Pharmaceutical Composition Comprising(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride

Concentration Tablet Unit Ingredient (% W/W) Weight (mg)(1R,5S)-1-(naphthalen-2- 25.0% 100 yl)-3-azabicyclo[3.1.0]hexanehydrochloride Lactose Monohydrate, NF 74.5% 298.0 Hypromellose, NF (as50/50 premix - RetaLac ®) Magnesium Stearate, NF  0.5% 2.0 (Hyqual ®Vegetable source) Total  100% 400

TABLE 8 Vessel 1 hr 2 hr 4 hr 6 hr 8 hr 12 hr 24 hr 1 20 29 47 60 73 — —2 22 34 53 68 79 — — 3 22 33 47 68 79 — — 4 20 30 47 64 74 — — 5 19 3043 59 69 — — 6 21 31 49 64 76 — — Ave 21 31 48 64 75 — — % RSD 5.5 6.67.3 5.7 5.0 — — NOTE: 12 and 24 hour pulls not performed

Example 9 Sustained Release Pharmaceutical Composition Comprising(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride

Concentration Tablet Unit Ingredient (% W/W) Weight (mg)(1R,5S)-1-(naphthalen-2- 25.0% 100 yl)-3-azabicyclo[3.1.0]hexanehydrochloride Lactose Monohydrate, NF 74.5% 298.0 Hypromellose, NF (as50/50 premix - RetaLac ®) Magnesium Stearate, NF  0.5% 2.0 (Hyqual ®Vegetable source) Total  100% 400

Batch has an approximate 50% dissolution release at 4 hours andapproximate 80% release at 8 hours.

1. A sustained release pharmaceutical composition comprising(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free orpharmaceutically acceptable salt form, wherein 40-60% of the(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane is released anddissolved within 4 hours or less as measured in 900 mL water using USPApparatus 2 paddle at 50 rpm and at 37° C.±0.5. 2-5. (canceled)
 6. Thecomposition of claim 1, wherein the composition comprises less than orequal to 5% w/w of the corresponding (−) enantiomer.
 7. The compositionof claim 1, wherein the composition comprises less than or equal to 2%w/w of the corresponding (−) enantiomer.
 8. The composition of claim 1,wherein the composition comprises less than or equal to 1% w/w of thecorresponding (−) enantiomer. 9-10. (canceled)
 11. The composition ofclaim 1, wherein the(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane is inpharmaceutically acceptable salt form and is(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride. 12.The composition of claim 1, wherein the composition comprises 100 mg to300 mg of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in freeor pharmaceutically acceptable salt form.
 13. (canceled)
 14. Thecomposition of claim 1, wherein the compositions comprises 100 mg to 200mg of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free orpharmaceutically acceptable salt form. 15-16. (canceled)
 17. Thecomposition of claim 1, wherein the composition comprises 10-30% w/w of(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free orpharmaceutically acceptable salt form.
 18. The composition of claim 1,wherein the composition further comprises hydroxypropyl methylcellulose.19. The composition of claim 18, wherein the composition comprises20-50% w/w of hydroxypropyl methylcellulose.
 20. The composition ofclaim 18, wherein the degree of methoxy substitution of thehydroxypropyl methylcellulose is 19-24%.
 21. The composition of claim18, wherein the degree of hydroxypropoxy substitution of thehydroxypropyl methylcellulose is 4-12%.
 22. The composition of claim 18,wherein the hydroxypropyl methylcellulose is hypromellose
 2208. 23. Thecomposition of claim 18, wherein the hydroxypropyl methylcellulose has anominal viscosity of 4,000 mPA·s.
 24. The composition of claim 18,wherein the hydroxypropyl methylcellulose has a viscosity of 2,600 to5,000 mPA·s.
 25. The composition of claim 1, wherein the compositionfurther comprises alpha-lactose monohydrate.
 26. The composition ofclaim 25, wherein the composition comprises 20-50% w/w of alpha-lactosemonohydrate.
 27. The composition of claim 25, wherein the compositioncomprises milled alpha-lactose monohydrate.
 28. The composition of claim1, wherein the composition comprises a co-processed mixture ofhydroxpropyl methylcellulose and alpha-lactose monohydrate.
 29. Thecomposition of claim 28, wherein the mixture comprises equal parts ofthe hydroxpropyl methylcellulose and alpha-lactose monohydrate.
 30. Thecomposition of claim 28, wherein the mixture comprises particles ofhydroxpropyl methylcellulose and alpha-lactose monohydrate with d₅₀(median diameter) in the range of 100 mm to 200 mm.
 31. The compositionof claim 28, wherein the mixture comprises particles of hydroxpropylmethylcellulose and alpha-lactose monohydrate wherein the particle sizedistribution is as follows: <63 mm≦25% <100 mm: 35% <250 mm≧80%.
 32. Thecomposition of claim 28, wherein the composition comprises 60-80% w/w ofthe mixture.
 33. The composition of claim 1, wherein the compositionfurther comprises a lubricant.
 34. The composition of claim 33, whereinthe lubricant is one or more of glyceryl behenate, magnesium stearate,talc, and sodium stearyl fumarate.
 35. The composition of claim 33,wherein the composition comprises 0.1 to 1% w/w of the lubricant. 36.The composition of claim 33, wherein the composition comprises 0.1 to 1%w/w of magnesium stearate. 37-45. (canceled)
 46. The composition ofclaim 1, wherein 60-90% of the(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane is released anddissolved within 8 hours or less as measured in 900 mL water using USPApparatus 2 paddle at 50 rpm and at 37° C.±0.5.